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Background: Infectious disease surveillance systems, which largely rely on diagnosed cases, underestimate the true incidence of SARS-CoV-2 infection, due to under-ascertainment and underreporting. We used repeat serologic testing to measure N-protein seroconversion in a well-characterized cohort of U.S. adults with no serologic evidence of SARS-CoV-2 infection to estimate the incidence of SARS-CoV-2 infection and characterize risk factors, with comparisons before and after the start of the SARS-CoV-2 vaccine and variant eras., Methods: We assessed the incidence rate of infection and risk factors in two sub-groups (cohorts) that were SARS-CoV-2 N-protein seronegative at the start of each follow-up period: 1) the pre-vaccine/wild-type era cohort (n=3,421), followed from April to November 2020; and 2) the vaccine/variant era cohort (n=2,735), followed from November 2020 to June 2022. Both cohorts underwent repeat serologic testing with an assay for antibodies to the SARS-CoV-2 N protein (Bio-Rad Platelia SARS-CoV-2 total Ab). We estimated crude incidence and sociodemographic/epidemiologic risk factors in both cohorts. We used multivariate Poisson models to compare the risk of SARS-CoV-2 infection in the pre-vaccine/wild-type era cohort (referent group) to that in the vaccine/variant era cohort, within strata of vaccination status and epidemiologic risk factors (essential worker status, child in the household, case in the household, social distancing)., Findings: In the pre-vaccine/wild-type era cohort, only 18 of the 3,421 participants (0.53%) had ≥1 vaccine dose by the end of follow-up, compared with 2,497/2,735 (91.3%) in the vaccine/variant era cohort. We observed 323 and 815 seroconversions in the pre-vaccine/wild-type era and the vaccine/variant era and cohorts, respectively, with corresponding incidence rates of 9.6 (95% CI: 8.3-11.5) and 25.7 (95% CI: 24.2-27.3) per 100 person-years. Associations of sociodemographic and epidemiologic risk factors with SARS-CoV-2 incidence were largely similar in the pre-vaccine/wild-type and vaccine/variant era cohorts. However, some new epidemiologic risk factors emerged in the vaccine/variant era cohort, including having a child in the household, and never wearing a mask while using public transit. Adjusted incidence rate ratios (aIRR), with the entire pre-vaccine/wild-type era cohort as the referent group, showed markedly higher incidence in the vaccine/variant era cohort, but with more vaccine doses associated with lower incidence: aIRR un/undervaccinated =5.3 (95% CI: 4.2-6.7); aIRR primary series only =5.1 (95% CI: 4.2-7.3); aIRR boosted once =2.5 (95% CI: 2.1-3.0), and aIRR boosted twice =1.65 (95% CI: 1.3-2.1). These associations were essentially unchanged in risk factor-stratified models., Interpretation: In SARS-CoV-2 N protein seronegative individuals, large increases in incidence and newly emerging epidemiologic risk factors in the vaccine/variant era likely resulted from multiple co-occurring factors, including policy changes, behavior changes, surges in transmission, and changes in SARS-CoV-2 variant properties. While SARS-CoV-2 incidence increased markedly in most groups in the vaccine/variant era, being up to date on vaccines and the use of non-pharmaceutical interventions (NPIs), such as masking and social distancing, remained reliable strategies to mitigate the risk of SARS-CoV-2 infection, even through major surges due to immune evasive variants. Repeat serologic testing in cohort studies is a useful and complementary strategy to characterize SARS-CoV-2 incidence and risk factors., Competing Interests: DISCLOSURES: Dr. Nash received consulting fees from Gilead Sciences, Inc. and Abbvie, Inc.

We examined the influence of racial/ethnic differences in socioeconomic position on COVID-19 seroconversion and hospitalization within a community-based prospective cohort enrolled in March 2020 and followed through October 2021 (N=6740). The ability to social distance as a measure of exposure to COVID-19, susceptibility to COVID-19 complications, and access to healthcare varied by race/ethnicity with non-white participants having more exposure risk and more difficulty with healthcare access than white participants. Participants with more (versus less) exposure had greater odds of seroconversion (aOR:1.64, 95% Confidence Interval [CI] 1.18-2.29). Participants with more susceptibility and more barriers to healthcare had greater odds of hospitalization (respective aOR:2.36; 1.90-2.96 and 2.31; 1.69-2.68). Race/ethnicity positively modified the association between susceptibility and hospitalization (aORnon-White:2.79, 2.06-3.78). Findings may explain the disproportionate burden of COVID-19 infections and complications among Hispanic and non-Hispanic Black persons. Primary and secondary prevention efforts should address disparities in exposure, COVID-19 vaccination, and treatment.

Background: Epidemiologic risk factors for incident SARS-CoV-2 infection as determined via prospective cohort studies greatly augment and complement information from case-based surveillance and cross-sectional seroprevalence surveys., Methods: We estimated the incidence of SARS-CoV-2 infection and risk factors in a well-characterized, national prospective cohort of 6,738 U.S. adults, enrolled March-August 2020, a subset of whom (n=4,510) underwent repeat serologic testing between May 2020 and January 2021. We examined the crude associations of sociodemographic factors, epidemiologic risk factors, and county-level community transmission with the incidence of seroconversion. In multivariable Poisson models we examined the association of social distancing and a composite score of several epidemiologic risk factors with the rate of seroconversion., Findings: Among the 4,510 individuals with at least one serologic test, 323 (7.3%, 95% confidence interval [CI] 6.5%-8.1%) seroconverted by January 2021. Among 3,422 participants seronegative in May-September 2020 and tested during November 2020-January 2021, we observed 161 seroconversions over 1,646 person-years of follow-up (incidence rate of 9.8 per 100 person-years [95%CI 8.3-11.5]). In adjusted models, participants who reported always or sometimes social distancing with people they knew (IRR always vs. never 0.43, 95%CI 0.21-1.0; IRR sometimes vs. never 0.47, 95%CI 0.22-1.2) and people they did not know (IRR always vs. never 0.64, 95%CI 0.39-1.1; IRR sometimes vs. never 0.60, 95%CI 0.38-0.97) had lower rates of seroconversion. The rate of seroconversion increased across tertiles of the composite score of epidemiologic risk (IRR medium vs. low 1.5, 95%CI 0.92-2.4; IRR high vs. low 3.0, 95%CI 2.0-4.6). Among the 161 observed seroconversions, 28% reported no symptoms of COVID-like illness (i.e., were asymptomatic), and 27% reported a positive SARS-CoV-2 diagnostic test. Ultimately, only 29% reported isolating and 19% were asked about contacts., Interpretation: Modifiable epidemiologic risk factors and poor reach of public health strategies drove SARS-CoV-2 transmission across the U.S during May 2020-January 2021., Funding: U.S. National Institutes of Allergy and Infectious Diseases (NIAID)., Competing Interests: CONFLICTS OF INTEREST: None declared